Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance
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Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.
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Some studies found that high TCR diversity in peripheral blood and tumors prior to immune checkpoint inhibitor therapy is predictive of effective treatment, while others found that increases in TCR clonality are a sign of effective therapy.
“some studies have found that high TCR diversity in peripheral blood and tumors prior to ICI therapy is predictive of effective treatment, others have pointed to ICI therapy-associated increases in TCR clonality, that is, enrichment of T cells with the same TCRs, as a sign of effective therapy (150, 157-161).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [157]
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Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features
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“However, these responses occur only in a minority of patients, and several studies have found that PD-1 expression, PD-L1 expression, MSI status, and mutation load are not efficient biomarkers for predicting the benefits of immune-checkpoint blockade (15, 69, 70).”
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Identification of essential genes for cancer immunotherapy
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Self-citationNeoadjuvant immune checkpoint blockade in high-risk resectable melanoma
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Self-citationGenomic correlates of response to immune checkpoint blockade
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Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade
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High response rate to PD-1 blockade in desmoplastic melanomas
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Self-citationT cell–induced CSF1 promotes melanoma resistance to PD1 blockade
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Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold
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Immuno-genomic landscape of osteosarcoma
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Self-citationComprehensive T cell repertoire characterization of non-small cell lung cancer
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Self-citationMetabolomic adaptations and correlates of survival to immune checkpoint blockade
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Common germline variants of the human APOE gene modulate melanoma progression and survival
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Trial watch: immune checkpoint blockers for cancer therapy
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T‐cell receptor and B‐cell receptor repertoire profiling in adaptive immunity
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Genomics and the Immune Landscape of Osteosarcoma
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- Authors
- Roh, W., Chen, P.-L., Reuben, A., Spencer, C. N., Prieto, P. A., Miller, J. P., Gopalakrishnan, V., Wang, F., Cooper, Z. A., Reddy, S. M., Gumbs, C., Little, L., Chang, Q., Chen, W.-S., Wani, K., De Macedo, M. P., Chen, E., Austin-Breneman, J. L., Jiang, H., Roszik, J., Tetzlaff, M. T., Davies, M. A., Gershenwald, J. E., Tawbi, H., Lazar, A. J., Hwu, P., Hwu, W.-J., Diab, A., Glitza, I. C., Patel, S. P., Woodman, S. E., Amaria, R. N., Prieto, V. G., Hu, J., Sharma, P., Allison, J. P., Chin, L., Zhang, J., Wargo, J. A., & Futreal, P. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- The University of Texas System (US)
- Corresponding author
- Roh, Whijae
- Chen, Pei-Ling
- Reuben, Alexandre
- Wargo, Jennifer A.
- Futreal, P. Andrew
- ORCID
- Roh, Whijae
- Chen, Pei-Ling
- Reuben, Alexandre
- Spencer, Christine N.
- Prieto, Peter A.
- Miller, John P.
- Gopalakrishnan, Vancheswaran
- Wang, Feng
- Cooper, Zachary A.
- Reddy, Sangeetha M.
- Gumbs, Curtis
- Little, Latasha
- Chang, Qing
- Chen, Wei-Shen
- Wani, Khalida
- Chen, Eveline
- Austin-Breneman, Jacob L.
- Jiang, Hong
- Roszik, Jason
- Tetzlaff, Michael T.
- Davies, Michael A.
- Gershenwald, Jeffrey E.
- Tawbi, Hussein
- Lazar, Alexander J.
- Hwu, Patrick
- Hwu, Wen-Jen
- Diab, Adi
- Glitza, Isabella C.
- Patel, Sapna P.
- Woodman, Scott E.
- Amaria, Rodabe N.
- Prieto, Victor G.
- Hu, Jianhua
- Sharma, Padmanee
- Allison, James P.
- Zhang, Jianhua
- Wargo, Jennifer A.
- Futreal, P. Andrew
- Venue
- Science Translational Medicine
- Published
- 2017-03
- Volume
- 9
- Issue
- 379
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC5819607
- OpenAlex
- W2593030814
- Cited by
- 859
- References
- 71
- Citations by year
- 2026: 27 · 2025: 60 · 2024: 82 · 2023: 109 · 2022: 155 · 2021: 153 · 2020: 117 · 2019: 59 · 2018: 51 · 2017: 43 · 2016: 1 · 2015: 1
- FWCI
- 32.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (award296776, 1K08CA160692-01A1,U54CA163125,T32CA009599,T32CA163185,R01 CA187076-02)
- National Cancer Institute (award296777, 2P30CA016672)
- Welch Foundation (award296778, G-0040)
- Cancer Prevention and Research Institute of Texas (award296779, R1205 01,R1204)
- Melanoma Research Alliance (award296780, Melanoma Research Alliance Team Science Award)
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (award296781)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- immune checkpoint blockade, CTLA-4 blockade, anti-PD-1 therapy, melanoma, treatment resistance, copy number loss, somatic mutation burden, immune gene expression, predictive biomarkers, sequential immunotherapy
- MeSH terms
- Biopsy, Clone Cells, Humans, Mutation, Neoplasms, T-Lymphocytes, Biomarkers, Tumor, Cohort Studies, Genome, Gene Dosage, Drug Resistance, Neoplasm, DNA Copy Number Variations, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
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